Abstract We have developed recombinant, replication-incompetent, genomic herpes simplex virus (HSV)-based vectors for gene transfer to the nervous system. In the previous period of funding we have demonstrated that HSV- mediated expression of neurotrophin-3 (NT-3), vascular endothelial growth factor (VEGF), or erythropoietin (EPO) in dorsal root ganglion (DRG) in vivo prevents the progression of neuropathy in mice with streptozotocin (STZ)-induced diabetes. In this competing renewal, we will continue to exploit the natural tropism of HSV vectors for peripheral sensory neurons of the (DRG) to further test the hypothesis that gene transfer of neuroprotective factors to the DRG by means of an HSV-based vector can be used to prevent the progression of diabetic neuropathy, with the ultimate aim of developing a therapy that will be effective for the treatment of human neuropathy. Four specific aims are described. (1) to determine whether HSV-mediated neuroprotective factor expression prevents the loss of DRG neurons in the streptozocin model of type 1 diabetes; (2) to examine the effect of HSV-mediated delivery of neuroprotective factors in the treatment of diabetic neuropathy in the db/db mouse model of type 2 diabetes; (3) to construct a vector with a regulatable switch to control transgene expression safely; and, (4) to test the effect of intermittent regulated protective factor expression on the progression of diabetic neuropathy in the STZ-diabetic and db/db mouse. Project Narrative Relevance to Public Health: Neuropathy is an important and often disabling complication of both type 1 and type 2 diabetes mellitus, and there are no currently available treatments that are effective in preventing the progression of the complication. These studies are designed to develop novel agents that could be used to treat the disease effectively.